1. Cross Reference to Related Applications
Expressly incorporated herein by reference are U.S. Pat. No. 5,801,193, and co-pending applications, U.S. Ser. Nos. 09/006,946; 09/007,308; 09/298,653; and PCT WO 98/46222.
2. Field of the Invention
This invention relates to the use of diterpene compounds, in particular hypoestoxides, derivatives and agonists thereof for anti-parasitic therapy and prophylaxis, wherein unexpected and beneficial results have been noted against nucleated infectious agents, among other things.
3. Background Art
Almost a third of the world's population lives in areas at risk of malaria, and according to estimates by World Health Organization (WHO), one to two million children in Sub-Saharan Africa die from the disease each year (WHO, Wkly Epidemiol Rec. 1997; 72: 269-76). This long-standing problem has not been addressed by conventional disclosures and remains a pressing issue in most of the developing nations of the world, in addition to demanding instant clinical study.
Malaria is caused by the protozoan parasites Plasmodium falciparum, P. vivax, P. ovale and P. malariae in humans and by P. berghei, P. chabaudi, P. yoelii, P. vinckei in rodents; P. knowlesi, P. cynomolgi in primates and P. Iophurae in avian. Malaria is the most deadly protozoan infection of humans. Hundreds of millions of cases of malaria occur annually and infections with P. falciparum the most virulent human malaria parasite, leads to millions of deaths each year (Walsh J. A. Annals of the New York Acad. Sciences 1989; 569: 1-16). Despite extensive control efforts, the incidence of malaria is not decreasing in most endemic areas of the world, and in some areas, it is clearly increasing (Oaks et al, eds. 1991: Washington, D.C.: National Academy Press). A major reason for the persistence of the severe malaria problem is the increasing resistance of parasites to available chemotherapeutic agents. Resistance to chloroquine, the most widely used antimalarial in the last 50 years, is now very common, and other available antimalarials are limited by resistance, high cost and toxicity (Olliaro et al; JMA 1996, 275:230-233).
Other antimalarials such as atrabrine dihydrochloride (quinacrine hydrochloride) produces a number of undesirable side effects, such as jaundice and gastrointestinal disturbances (Bogitsh, B. J. and Chen, T. C. eds. Human Parasitology, 2nd edition, 1998:Academic Press, San Diego, London, Boston, New York, etc.). Thus, the development of antimalarial drugs must be a continuous process, and requires both theoretical and clinical attention urgently.